Neovascularization in response to ischemia is an important repair process, which is severely compromised in the setting of chronically elevated cholesterol. Therapeutic neovascularization trials have revealed dramatically reduced responses in hypercholesterolemic patients; however, there is little information on the effects of hypercholesterolemia on arteriogenesis. Arteriogenesis, the outward remodeling of collateral vessels that form bridges between arterial networks, is critical for recovery of blood perfusion to the ischemic tissue after occlusion. Collateral remodeling is driven by a sudden increase in hemodynamic forces, especially shear stress, resulting from the drastic increase in flow through collaterals. This increase in shear stress is sensed by mechanosensory proteins expressed in endothelial cells (ECs), which initiate signal transduction pathways that induce processes such as cell proliferation and inflammation. Despite significant efforts to increase collateral growth and perfusion recovery in the setting of ischemia using small molecules and gene therapy approaches, results have been largely disappointing, underscoring the importance of studies on understanding the molecular mechanisms that drive arteriogenesis. Recently published work from our group, coupled with nascent observations provided in this application, identify the signaling protein adaptor protein Src homologous and collagen protein (Shc) as an essential regulator of neovascularization. To better understand the role of Shc in neovascularization, three interrelated aims are proposed. Aim 1 will determine the role of Shc in neovascularization in response to ischemia in the setting of hypercholesterolemia. Aim 2 will determine the role of Shc in endothelial mechanotransduction under defined collateral hemodynamic conditions in vitro. Aim 3 will determine the molecular determinants in Shc that facilitate neovascularization. Experiments proposed in this proposal will contribute to our understanding of molecular mechanisms of arteriogenesis and collateral remodeling. Elucidation of some of the signals that regulate post-ischemic neovascularization is needed in order to develop therapeutic strategies for diseases such as peripheral vascular disease, arteriosclerosis and wound healing.